Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome

Abstract

Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

Germline Variants and Characteristic Features of Hereditary Hematological Malignancy Syndrome

“…Future development of a hematologic tumor testing panel that is also useful in detecting refractory cytopenia and the risk of relapse refractoriness after leukemia-directed therapy is warranted. Extensive sequencing technologies, such as whole exome sequencing (WES), allow for the investigation of new candidate genetic abnormalities, including germline gene variants, at once, and are expected to be utilized more than targeted NGS panels in the future [ 4 , 251 ]. There is a growing need for the expert consultation and clinical surveillance of patients with a germline predisposition to hematologic malignancies [ 252 ].…”

“…However, in some cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), a hereditary (mainly autosomal dominant) predisposition has been observed [ 2 , 3 ]. Typically, a family in which two or more first- or second-degree relatives have developed acute leukemia (AL), myeloid malignancies, characteristic cytopenias, or either MDS or AML, is defined as “familial MDS/AML”, or, more broadly, hereditary hematologic malignancy syndrome (HHMS) [ 4 , 5 , 6 ]. The field of HHMS has gained increasing recognition among clinicians and scientists worldwide.…”

Case report: A familial B-acute lymphoblastic leukemia associated with a new germline pathogenic variant in PAX5. The first report in Mexico

“…However, risk alleles may be present in patients without clinical findings, suggesting hereditary hematologic malignancy syndromes. Guijarro F et al (25) identified pathogenic or likely pathogenic variants in ATM, DDX41, CHEK2, FANCA, FANCM, SBDS, DNAJC21, and CSF3R in 288 acute myeloid patients without criteria that would suggest the presence of hereditary hematologic malignancy syndromes. The existence of de novo or low-penetrance variants, late-onset disease, and incomplete family history contributes to a lack of clinical suspicion (26).…”

Characteristics and clinical outcomes of patients with myeloid malignancies and DDX41 variants

“…The identification of germline mutations predisposing to an increased risk of myeloid neoplasms is a growing field of interest 1 . A familial or personal history of cancer or pre‐existing cytopenia(s), together with specific clinical findings and an early age of onset of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) are potentially suggestive of an inherited mutation in a gene predisposing to myeloid malignancies, 2 although these risk factors are not always apparent 3 . As a result of this increasing knowledge, the revised 4th edition of the World Health Organization (WHO) classification of hematopoietic and lymphoid tissues published in 2016 recognized myeloid neoplasms with germline predisposition as distinct disease entities 4 .…”